Project 3: Modeling and overcoming resistance to melanoma immunotherapy

项目3摘要 我们已经开始在确定导致对抗-HCV的原发性和获得性耐药性的机制方面取得进展， 分子水平的PD-1/L1治疗。在这个项目中，我们建议描述它们的生物学特征， 克服基于机械理解的阻力，并研究如何利用这些知识提高 病人护理在目标1中，我们将开发体外和体内模型来研究分子定义的 抗性机制，目的是提供对它们如何介导 阻力这是基于我们发现的干扰素基因中的纯合性功能丧失（LoF）突变。 (IFN)受体途径和抗原呈递机制（APM）在原发性和 对PD-1阻断治疗获得性耐药，这两个结果都得到了其他组数据的证实。与此 信息，我们将能够测试组合方法，以克服抗PD-1/L1的耐药性 疗法这些方法包括旨在诱导局部IFN应答，从而激活该途径 下游，如JAK 1/2敲除模型中的toll样受体（TLR）或MDA 5激动剂，以及激活 在B2 M敲除模型中的自然杀伤（NK）细胞。在目标2中，我们将研究一种新的癌细胞--内源性 p21相关激酶4（PAK 4）表达介导的T细胞排斥机制，我们 最近通过比较患者T细胞丰富和T细胞缺乏的活检组织中的基因表达， 黑色素瘤患者接受抗PD-1治疗我们将研究导致T细胞排斥的机制 在小鼠模型中，我们将分析从患者获得的活检组织中的机制， 在一项临床试验中，参与了PAK 4抑制剂KPT-9274和抗PD-1抗体纳武单抗的组合。 这两个目标的样本分析将受益于与其他两个目标的研究人员的合作 P01的项目和核心。总之，本项目将分析治疗的定义机制， 抵抗癌症免疫疗法，以提供更好的了解他们的影响，并显示如何 利用合理设计的组合研究克服阻力。 1

PROJECT 3 ABSTRACT We have started to make progress in defining mechanisms that lead to primary and acquired resistance to anti- PD-1/L1 therapy at the molecular level. In this Project, we propose to characterize their biology, discover how to overcome resistance based on mechanistic understanding, and study how this knowledge can improve patient care. In Aim 1, we will develop in vitro and in vivo models to study the biology of molecularly-defined resistance mechanisms with the goal of providing full mechanistic understanding of how they mediate resistance. This is based on our discovery of homozygous loss of function (LoF) mutations in the interferon (IFN) receptor pathway and in the antigen presenting machinery (APM) in biopsies of patients with primary and acquired resistance to PD-1 blockade therapy, both confirmed with data from other groups. With this information, we will be in the position to test combination approaches to overcome resistance to anti-PD-1/L1 therapy. These include approaches aimed at inducing a local IFN response that may activate this pathway downstream, such as toll-like receptor (TLR) or MDA5 agonists in JAK1/2 knockout models, and activating natural killer (NK) cells in B2M knockout models. In Aim 2, we will study a new cancer cell-intrinsic mechanisms of T cell exclusion mediated by the expression of the p21 associated kinase 4 (PAK4), which we have recently uncovered by comparing gene expression in T cell-rich versus T cell-poor biopsies of patients with melanoma on therapy with anti-PD-1. We will examine the mechanisms leading to T cell exclusion induced by PAK4 in mouse models, and we will analyze the mechanisms in biopsies obtained from patients enrolled in a clinical trial combining the PAK4 inhibitor KPT-9274 and the anti-PD-1 antibody nivolumab. Sample analyses for the two aims will benefit from the collaboration with investigators from the other two projects and cores of this P01. In conclusion, this Project will analyze defined mechanisms of therapeutic resistance to cancer immunotherapy to provide improved understanding on their effects, and show how to overcome the resistance using rationally designed combination studies. 1